DE69908335T2 - TRIAZOLPURINE DERIVATIVES, MEDICAL COMPOSITIONS THAT CONTAIN THE ADENOSINE A3 RECEPTOR COMPATIBILIZING AGENT AND ASTHMA MEDICINE - Google Patents

Abstract

Triazolopurine derivatives represented by general formula (1), wherein R<1> and R<2> each is as defined in the description; and A represents a group represented by (a), (b), or (c)(wherein R<3> is as defined in the description). These compounds have an affinity for an adenosine A3 receptor. A medicinal composition containing any of these is hence used as an adenosine A3 receptor compatibilizing agent or an asthmatic remedy. <CHEM>

Description

[Technical field]

The present invention relates to a new triazolopurine derivative, which shows adenosine A3 receptor affinity a pharmaceutical composition containing the derivative, a Adenosine A3 receptor ligand and a cure for asthma.

[State of the art]

J. Heterocyclic Chem., 31, 1171 (1994) discloses that 2-aryl-8-fluorobenzyl-1,2,4-triazolo [5,1-i] purine as Adenosine A2 receptor ligand useful is.

An object of the present invention is to provide a new compound with an affinity for an adenosine A3 receptor.

DISCLOSURE OF THE INVENTION

worin R¹ eine Alkyl-Gruppe oder eine Phenyl-Gruppe bedeutet, die optional mit einer Niederalkyl-Gruppe substituiert ist;
R² bedeutet eine Pyridyl-Gruppe, eine Furyl-Gruppe, eine Thienyl-Gruppe, eine Niederalkyl-Gruppe, eine Phenyl-Niederalkyl-Gruppe, die optional 1 bis 3 Niederalkoxy-Gruppen als Substituenten aufweist, eine Styryl-Gruppe, die optional 1 bis 3 Niederalkoxy-Gruppen als Substituenten aufweist, eine Naphthyl-Gruppe, die optional eine Hydroxy-Gruppe als Substituenten aufweist, oder eine Phenyl-Gruppe, die optional 1 bis 3 Gruppen als Substituenten aufweist, ausgewählt aus einer Niederalkyl-Gruppe, Niederalkoxy-Gruppe, Nitro-Gruppe, Hydroxy-Gruppe, Amino-Gruppe, N-Niederalkylamino-Gruppe, N,N-Diniederalkylamino-Gruppe, N-Phenyl-Niederalkylamino-Gruppe, N,N-Bisphenyl-Niederalkylamino-Gruppe, Phenyl-Gruppe, Phenoxy-Gruppe, Phenyl-Niederalkoxy-Gruppe, Halogen-substituierten Niederalkyl-Gruppe, Halogen-substituierten Niederalkoxy-Gruppe, Diniederalkylphosphorylmethyl-Gruppe, Niederalkylthio-Gruppe, Niederalkoxy-Niederalkyl-Gruppe, Phenyl-Niederalkoxy-Niederalkyl-Gruppe und einem Halogenatom;
und A bedeutet eine Gruppe:

worin R³ eine Niederalkyl-Gruppe oder eine Phenyl-Niederalkyl-Gruppe bedeutet.The triazolopurine derivative according to the invention is represented by the general formula (1):

wherein R ^{1 represents} an alkyl group or a phenyl group which is optionally substituted with a lower alkyl group;
R ^{2 represents} a pyridyl group, a furyl group, a thienyl group, a lower alkyl group, a phenyl lower alkyl group which optionally has 1 to 3 lower alkoxy groups as substituents, a styryl group which optionally has 1 has up to 3 lower alkoxy groups as substituents, a naphthyl group which optionally has a hydroxyl group as substituents, or a phenyl group which optionally has 1 to 3 groups as substituents selected from a lower alkyl group, lower alkoxy group , Nitro group, hydroxyl group, amino group, N-lower alkylamino group, N, N-di-lower alkylamino group, N-phenyl-lower alkylamino group, N, N-bisphenyl-lower alkylamino group, phenyl group, phenoxy Group, phenyl-lower alkoxy group, halogen-substituted lower alkyl group, halogen-substituted lower alkoxy group, di-lower alkylphosphorylmethyl group, lower alkylthio group, lower alkoxy-lower alkyl group, phenyl-lower alkoxy-lower alkyl group and a halogen atom;
and A means a group:

wherein R ^{3 represents} a lower alkyl group or a phenyl lower alkyl group.

The tiazolopurine derivative according to the invention is a new connection that has never been described in reference documents has been.

ist. In dem Fall ist R² bevorzugt eine Pyridyl-Gruppe, eine Furyl-Gruppe, eine Styryl-Gruppe, eine Naphthyl-Gruppe, die optional eine Hydroxy-Gruppe als Substituenten aufweist, eine Phenyl-Gruppe, die optional eine Gruppe als Substituenten aufweist, ausgewählt aus einer Niederalkyl-Gruppe, N-Niederalkylamino-Gruppe, N,N-Diniederalkylamino-Gruppe, N-Phenyl-Niederalkylamino-Gruppe, N,N-Bisphenyl-Niederalkylamino-Gruppe, Phenyl-Gruppe, Phenoxy-Gruppe, Phenyl-Niederalkoxy-Gruppe, Halogen-substituierten Niederalkyl-Gruppe, Halogen-substituierten Niederalkoxy-Gruppe, Diniederalkylposphorylmethyl-Gruppe, Niederalkylthio-Gruppe, Hydroxy-Gruppe und einem Halogenatom, eine Phenyl-Gruppe, substituiert mit einer Hydroxyl-Gruppe und einem Halogenatom, oder eine Phenyl-Gruppe mit 1 bis 3 Niederalkoxy-Gruppen als Substituenten.According to the invention, a triazolopurine derivative is particularly preferred in which A is a group:

is. In that case, R ^{2 is} preferably a pyridyl group, a furyl group, a styryl group, a naphthyl group which optionally has a hydroxyl group as a substituent, a phenyl group which is optional has a group as a substituent selected from a lower alkyl group, N-lower alkylamino group, N, N-di-lower alkylamino group, N-phenyl-lower alkylamino group, N, N-bisphenyl-lower alkylamino group, phenyl group, phenoxy Group, phenyl-lower alkoxy group, halogen-substituted lower alkyl group, halogen-substituted lower alkoxy group, di-lower alkylphosphorylmethyl group, lower alkylthio group, hydroxy group and a halogen atom, a phenyl group substituted with a hydroxyl group and a halogen atom, or a phenyl group with 1 to 3 lower alkoxy groups as substituents.

• (a) eine Verbindung, worin R¹ eine Alkyl-Gruppe oder eine Niederalkyl-substituierte Phenyl-Gruppe ist, und R² ist eine Phenyl-Gruppe;
• (b) eine Verbindung, worin R¹ eine n-Butyl-Gruppe ist, und R² ist eine Pyridyl-Gruppe, eine Furyl-Gruppe, eine Styryl-Gruppe, eine Naphthyl-Gruppe, die optional eine Hydroxy-Gruppe als Substituenten aufweist, eine Phenyl-Gruppe, die optional eine Gruppe als Substituenten aufweist, ausgewählt aus einer Niederalkyl-Gruppe, N-Niederalkylamino-Gruppe, N,N-Diniederalkylamino-Gruppe, N-Phenyl-Niederalkylamino-Gruppe, N,N-Bisphenyl-Niederalkylamino- Gruppe, Phenyl-Gruppe, Phenoxy-Gruppe, Phenyl-Niederalkoxy-Gruppe, Halogen-substituierten Niederalkyl-Gruppe, Halogen-substituierten Niederalkoxy-Gruppe, Diniederalkylphosphorylmethyl-Gruppe, Niederalkylthio-Gruppe, Hydroxy-Gruppe und einem Halogenatom, eine Phenyl-Gruppe, substituiert mit einer Hydroxy-Gruppe und einem Halogenatom, oder eine Phenyl-Gruppe mit 1 bis 3 Niederalkoxy-Gruppen als Substituenten, und
• (c) eine Verbindung, worin R¹ eine Phenyl-Gruppe ist, und R² ist eine Phenyl-Gruppe mit 3 Niederalkoxy-Gruppen.

A particularly preferred compound is a compound selected from the group of the following compounds (a), (b) and (c):

• (a) a compound wherein R ^{1 is} an alkyl group or a lower alkyl substituted phenyl group and R ² is a phenyl group;
• (b) a compound wherein R ^{1 is} an n-butyl group and R ² is a pyridyl group, a furyl group, a styryl group, a naphthyl group, which optionally has a hydroxy group as a substituent , a phenyl group which optionally has a group as a substituent selected from a lower alkyl group, N-lower alkylamino group, N, N-di-lower alkylamino group, N-phenyl-lower alkylamino group, N, N-bisphenyl-lower alkylamino - Group, phenyl group, phenoxy group, phenyl-lower alkoxy group, halogen-substituted lower alkyl group, halogen-substituted lower alkoxy group, di-lower alkylphosphorylmethyl group, lower alkylthio group, hydroxy group and one halogen atom, a phenyl group , substituted with a hydroxy group and a halogen atom, or a phenyl group with 1 to 3 lower alkoxy groups as substituents, and
• (c) a compound wherein R ^{1 is} a phenyl group and R ² is a phenyl group having 3 lower alkoxy groups.

• (i) eine Verbindung, worin R¹ eine Niederalkyl-Gruppe und R² eine Phenyl-Gruppe ist, und
• (ii) eine Verbindung, worin R¹ eine n-Butyl-Gruppe ist, und R² ist eine Naphthyl-Gruppe, die optional eine Hydroxy-Gruppe als Substituenten aufweist, eine Phenyl-Gruppe, die optional als Substituenten eine Gruppe aufweist, ausgewählt aus einer Niederalkyl-Gruppe, N,N-Diniederalkylamino-Gruppe, N-Phenyl-Niederalkylamino-Gruppe, Phenyl-Gruppe, Phenoxy-Gruppe, Phenyl-Niederalkoxy-Gruppe, Halogen-substituierten Niederalkyl-Gruppe, Halogen-substituierten Niederalkoxy-Gruppe, Diniederalkylphosphorylmethyl-Gruppe, Niederalkylthio-Gruppe und einem Halogenatom, eine Phenyl-Gruppe, substituiert mit einer Hydroxy-Gruppe und einem Halogenatom, oder eine Phenyl-Gruppe mit 1 bis 3 Niederalkoxy-Gruppen als Substituenten.

A more preferred compound is a compound selected from the group of the following compounds (i) and (ii):

• (i) a compound wherein R ^{1 is} a lower alkyl group and R ^{2 is} a phenyl group, and
• (ii) a compound wherein R ^{1 is} an n-butyl group and R ² is a naphthyl group which optionally has a hydroxy group as a substituent, a phenyl group which optionally has a group as a substituent from a lower alkyl group, N, N-di-lower alkylamino group, N-phenyl-lower alkylamino group, phenyl group, phenoxy group, phenyl-lower alkoxy group, halogen-substituted lower alkyl group, halogen-substituted lower alkoxy group, Diniederalkylphosphorylmethyl group, Niederalkylthio group and a halogen atom, a phenyl group substituted with a hydroxy group and a halogen atom, or a phenyl group with 1 to 3 lower alkoxy groups as substituents.

The compound of the invention is preferred a compound consisting of 5-n-butyl-8- (3,4,5-trimethoxyphenyl) -1H-1,2,4-triazolo [5,1-i] purine, 5-n-butyl-8- (4-chlorophenyl) -1H-1,2,4-triazolo [5,1-i] purine, 5-n-butyl-8- (4-methoxyphenyl) -1H- 1,2,4-triazolo [5,1-i] puirin, 5-n-butyl-8- (N, N-dimethylamino) phenyl] -1H-1,2,4-triazolo [5,1-i] purine, 5-n-butyl-8- (4-propoxyphenyl) -1H-1,2,4-triazolo [5,1-i] purine, 5-n-butyl-8- (4-ethoxyphenyl) -1H-1,2,4-triazolo [5,1-i] purine, 8- (4-biphenylyl) -5-n-butyl-1H-1,2,4-triazolo [5,1-i] puirine, 5-n-butyl-8- (4-trifluoromethylphenyl) -1H-1, 2,4-triazolo [5,1-i] purin and 5-n-pentyl-8-phenyl-1H-1,2,4-triazolo [5,1-i] purine is selected and is particularly preferably a compound consisting of 5-n-butyl-8- (4-methoxyphenyl) -1H-1,2,4-triazolo [5,1-i] purine, 5-n-butyl-8- (3,4,5-trimethoxyphenyl) -1H-1,2,4-triazolo [5,1-i] purin and 8- (4-biphenylyl) -5-n-butyl-1H-1,2,4-triazolo [5,1-i] purine is selected.

The triazolopurine derivative of the present invention is expected to be an antihypertensive Agent, anti-allergic agent, anti-inflammatory agent, remedy for ischemic heart disease, Remedies for leukemia, itching inhibitory agent, expectorant Remedies, cough medicine, remedies for asthma and analgesic are used because it is a connection that is excellent because of its affinity towards one Adenosine A3 receptor is capable of using an Adenosine A3 receptor to tie.

Accordingly, the present invention provides also a the triazolopurine derivative described above and one pharmaceutically acceptable carrier comprehensive pharmaceutical composition.

Specifically, the present invention a the triazolopurine derivative described above as an active ingredient comprising adenosine A3 receptor ligands and a triazolopurine derivative as an active ingredient comprehensive cure for Asthma ready.

BEST EMBODIMENT OF THE INVENTION

According to the invention, the lower alkyl group includes z. B. straight-chain or branched lower alkyl groups with 1 to 6 Carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, Pentyl and hexyl.

The alkyl group includes e.g. B. Alkyl groups with 7 to 8 carbon atoms, such as heptyl and octyl, additionally to the lower alkyl groups described above.

The lower alkoxy group includes e.g. B. straight-chain or branched lower alkoxy groups with 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy and Hexyloxy.

The halogen atom includes fluorine, Chlorine, bromine or iodine.

The pyridyl group includes 2-pyridyl, 3-pyridyl and 4-pyridyl.

The furyl group includes 2-furyl and 3-furyl.

The thienyl group includes the 2-thienyl group and the 3-thienyl group on.

The naphthyl group, which is optional has a hydroxy group as a substituent, e.g. B. 1-naphthyl, 2-naphthyl, 1-hydroxy-2-naphthyl, 3-hydroxy-2-naphthyl, 4-hydroxy-2-naphthyl, 5-hydroxy-2-naphthyl, 6-hydroxy-2-naphthyl, 7-hydroxy-2-naphthyl, 8-hydroxy-2-naphthyl, 2-hydroxy-1-naphthyl, 3-hydroxy-1-naphthyl, 4-hydroxy-1-naphthyl, 5-hydroxy-1-naphthyl, 6-hydroxy-1-naphthyl, 7-hydroxy-1-naphthyl and 8-hydroxy-1-naphthyl.

The phenyl, which is optionally a group selected from lower alkyl group, lower alkoxy group, nitro group, hydroxyl group, amino group, N-lower alkylamino group, N, N-di-lower alkylamino group, N-phenyl-lower alkylamino group , N, N-bisphenyl-lower alkylamino group, phenyl group, phenoxy group, phenyl-lower alkoxy group, halogen-substituted lower alkyl group, halogen-substituted lower alkoxy group, di-lower alkylphosphorylmethyl group, lower alkylthio group, lower alkoxy group , Phenyl-lower alkoxy-lower alkyl group and halogen atom as a substituent includes e.g. B. phenyl groups, which optionally have 1 to 3 substituents, such as 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-t-butylphenyl, 4 -Pentylphenyl, 4-hexylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4-diethylphenyl, 3 , 4-dipropylphenyl, 3,4-dibutylphenyl, 3,4-dipentylphenyl, 3,4-dihexylphenyl, 3,4,5-trimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3 , 6-trimethylphenyl, 2,4,6-trimethylphenyl, 2,4,5-trimethylphenyl, 3,4,5-triethylphenyl, 3,4,5-tripropylphenyl, 3,4,5-tributylphenyl, 3,4,5 -Tripentylphenyl, 3,4,5-trihexylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 2,3-dimethoxyphenyl, 2 , 4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,4-dipropoxyphenyl, 3,4-dibutoxyphenyl, 3,4-dipentyloxyphenyl, 3,4-dihexyloxyphenyl, 3,4,5-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 3,4,5-triethoxyphenyl, 3,4,5-tripropoxyphenyl, 3,4,5-tributoxyphenyl, 3,4,5-tripentyloxyphenyl, 3, 4,5-trihexyloxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3, 5-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 2,3,4-trihydroxyphenyl, 2,3,5-trihydroxyphenyl, 2,3,6-trihydroxyphenyl, 2,4,6-trihydroxyphenyl, 2,4,5- Trihydroxyphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,3-dinitrophenyl, 2,4-dinitrophenyl, 2,5-dinitrophenyl, 2,6-dinitrophenyl, 3,4-dinitrophenyl, 3,5-dinitrophenyl, 3,4,5-trinitrophenyl, 2,3,4-trinitrophenyl, 2,3,5-trinitrophenyl, 2,3,6-trinitrophenyl, 2,4,6-trinitrophenyl, 2,3,5-trinitrophenyl, 2- Aminophenyl, 3-aminophenyl, 4-aminophenyl, 3,4-diaminop henyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,4-difluorophenyl, 2,4-dibromophenyl, 2, 4-diiodophenyl, 3,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 4-methoxy-3-methylphenyl, 4-methoxy-2-methylphenyl, 3-methoxy-2-methylphenyl, 4-methoxy-3, 5-dimethylphenyl, 4-hydroxy-3-methylphenyl, 4-hydroxy-2-methylphenyl, 3-hydroxy-2-methylphenyl, 2-hydroxy-4-methylphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-3, 5-dimethylphenyl, 3,5-di-t-butyl-4-hydroxyphenyl, 4-hydroxy-3,5-dimethoxyphenyl, 3,5-dihydroxy-4-methoxyphenyl, 4-chloro-3-methoxyphenyl, 3-chloro 4-methoxyphenyl, 4-chloro-2-hydroxyphenyl, 4-chloro-3-hydroxyphenyl, 4-chloro-3-methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-3,5-dimethoxyphenyl, 4-chloro 3,5-dimethylphenyl, 4- (N-methylamino) phenyl, 4- (N-ethylamino) p henyl, 4- (N-propylamino) phenyl, 4- (N-butylamino) phenyl, 4- (N-pentylamino) phenyl, 4- (N-hexylamino) phenyl, 3- (N-methylamino) phenyl, 2- ( N-methylamino) phenyl, 4- (N, N-dimethylamino) phenyl, 4- (N, N-diethylamino) phenyl, 4- (N, N-dipropylamino) phenyl, 4- (N, N-dibutylamino) phenyl, 4- (N, N-dipentylamino) phenyl, 4- (N, N-dihexylamino) phenyl, 3- (N, N-dimethylamino) phenyl, 2- (N, N-dimethylamino) phenyl, 4- (N-benzylamino ) phenyl, 4 - [(N- (2-phenylethyl) amino] phenyl, 4 - [(N- (3-phenylpropyl) amino] phenyl, 4 - [(N- (4-phenylbutyl) amino] phenyl, 4- [(N- (5-phenylpentyl) amino] phenyl, 4 - [(N- (6-phenylhexyl) amino] phenyl, 3- (N-benzylamino) phenyl, 2- (N-benzylamino) phenyl, 4- (N , N-dibenzylamino) phenyl, 4- [N, N-dibenzylamino) phenyl, 4- [N, N-bis (2-phenylethyl) amino] phenyl, 4- [N, N-bis (3-phenylpropyl) amino] phenyl, 4- [N, N-bis (4-phenylbutyl) amino] phenyl, 4- [N, N-bis (5-phenylpentyl) amino] phenyl, 4- [N, N-bis (6-phenylhexyl) amino ] phenyl, 3- (N, N-dibenzylamino) phenyl, 2- (N, N-dibenzylamino) phenyl, 4-biphenylyl, 3-biphenylyl, 2-biphenylyl, 4-phenoxy phenyl, 3-phenoxyphenyl, 2-phenoxyphenyl, 4-benzyloxyphenyl, 4- (2-phenylethoxy) phenyl, 4- (3-phenylpropoxy) phenyl, 4- (4-phenylbutoxy) phenyl, 4- (5-phenylpentyloxy) phenyl, 4- (6-phenylhexyloxy) phenyl, 3-benzyloxyphenyl, 2-benzyloxyphenyl, 4-trifluoro methylphenyl, 4-pentafluoroethylphenyl, 4-heptafluoropropylphenyl, 4-nonafluorobutylphenyl, 4-undecafluorpentylphenyl, 4-tridecafluorhexylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-pentafluorophenyl, 4-pentafluorophenyl 4-Tridecafluorhexyloxyphenyl, 3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-Dimethoxyphosphorylmethylphenyl, 4-diethoxyphosphorylmethylphenyl, 4-Dipropoxyphosphorylmethylphenyl, 4-Dibutoxyphosphorylmethylphenyl, 4-Dipentyloxyphosphorylmethylphenyl, 4-Dihexyloxyphosphorylmethylphenyl, 3-diethoxyphosphorylmethylphenyl, 2-diethoxyphosphorylmethylphenyl, 4-methylthiophenyl, 4- Ethylthiophenyl, 4-propylthiophenyl, 4-butylthiophenyl, 4-pentylthiophenyl, 4-hexylthiophenyl, 3-methylthiophenyl, 2-methylthiophenyl, 4-methoxymethylphenyl, 3-methoxymethylphenyl, 2-methoxymethylphenyl, 4-ethoxymoxphenymphenyl, 4-methoxymylphenyl, 4-methoxymethylphenyl 4-Pentyloxymethylphenyl, 4-hexyloxymethylphenyl, 4- (2-methoxyethyl) phenyl, 4- (3-methoxypropyl) phenyl, 4- (4-methoxybutyl) phenyl), 4- (5-methoxypentyl) phenyl, 4- (6-methoxymexyl) phenyl, 4-benzyloxymethylphenyl, 3-benzyloxymethylphenyl, 2-benzyloxymethylphenyl, 4- (2-benzyloxyethyl) phenyl, 4- (3-benzyloxypropyl) phenyl, 4- (4-benzyloxybutyl) phenyl, 4- (5-benzyloxypentyl) phenyl, 4- (6-benzyloxyhexyl) phenyl, 4- (2-phenylethoxymethyl) phenyl, 4- (3-phenylpropoxymethyl) phenyl, 4- (4-phenylbutoxymethyl) phenyl, 4- (5-phenylpentyloxymethyl) phenyl and 4- (6-phenylhexyloxymethyl) phenyl a.

The phenyl group, optionally with a lower alkyl group is substituted, e.g. B. 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4,5-trimethylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-butylphenyl, 4-pentylphenyl and 4-hexylphenyl additionally to the phenyl group.

The phenyl lower alkyl group includes e.g. B. Benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl or 6-phenylhexyl.

The phenyl lower alkyl group, the optionally has 1 to 3 lower alkoxy groups as substituents, includes e.g. B. 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, 4-ethoxybenzyl, 4-propoxybenzyl, 4-butoxybenzyl, 4-pentyloxybenzyl, 4-hexyloxybenzyl, 2- (4-methoxyphenyl) ethyl, 3- (4-methoxyphenyl) propyl, 4- (4-methoxyphenyl) butyl, 5- (4-methoxyphenyl) pentyl, 6- (4-methoxyphenyl) hexyl, 2- (3,4,5-trimethoxyphenyl) ethyl, 3- (3,4,5-trimethoxyphenyl) propyl, 4- (3,4,5-trimethoxyphenyl) butyl, 5- (3,4,5-trimethoxyphenyl) pentyl and 6- (3,4,5-trimethoxyphenyl) hexyl in addition to that described above Phenyl-lower alkyl group.

The styryl group, which is optional 1 has up to 3 lower alkyl groups as substituents, z. B. 2-methoxystyryl, 3-methoxystyryl, 4-methoxystyryl, 2,4-dimethoxystyryl, 3,4-dimethoxystyryl, 3,5-dimethoxystyryl, 3,4,5-trimethoxystyryl, 4-ethoxystyryl, 4-propoxystyryl, 4-butoxystyryl, 4-pentyloxystyryl or 4-hexyloxystyryl in addition to the styryl group.

Specific examples of the compounds of the invention (1) are shown in Tables 1 to 8. In the corresponding tables Me denotes a methyl group, Et denotes an ethyl group, n-Pr denotes an n-propyl group, n-Bu denotes an n-butyl group, n-Pre denotes an n-pentyl group, n-Hx denotes an n-hexyl group, n-Hp denotes a heptyl group, n-Oc denotes an n-octyl group, Ph denotes a phenyl group and Bn denotes a benzyl group.

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

worin R¹, R² und A wie oben definiert sind, und Z eine Niederalkyl-Gruppe darstellt.The compound (1) according to the invention can be prepared according to the following reaction scheme 1. Reaction scheme 1

wherein R ¹ , R ² and A are as defined above, and Z represents a lower alkyl group.

First one is through the formula (2) represented compound with a represented by formula (3) Orthoester derivative implemented to an imino ester represented by the formula (4) to obtain.

This reaction is admitted of the orthoester derivative (3) in an equimolar amount or more, based on the amount of the compound (2) and heating at a temperature inside a range of 50 ° C up to the reflux temperature for about 10 minutes to 5 hours in the absence of a solvent or in one inert solvents carried out. As the inert solvent can z. B. N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), methanol, diphenyl ether, xylene and diethylene glycol dimethyl ether be used.

The resulting iminoester derivative (4) is reacted with an acylhydrazine derivative (5) after the Ester derivative according to one usual Process has been purified or not to the compounds of the invention (1) to get.

This reaction is carried out by adding the acylhydrazine derivative (5) in an equimolar amount or more based on the amount of the iminoester derivative (4) in an inert solvent, optionally adding a catalytic amount of 1,8-diazabicyclo [5.4 , 0] -7-undecene and heating at a temperature within a range from 50 ° C to the reflux temperature for about 1 to 50 hours. The inert Solvent includes the same solvents as described above. If necessary, the reaction solution can be made alkaline by adding an aqueous sodium hydroxide solution and an aqueous potassium hydroxide solution, and can also be reacted at a temperature within a range from 0 ° C to room temperature for 10 minutes to 5 hours after the completion of the heating reaction.

worin R¹, R² und A wie oben definiert sind, und R^1a einen von R¹ verschiedenen Substituenten innerhalb desselben Definitionsbereichs wie für R¹ darstellt.The substituents represented by R ^{1 of} the compound (1) of the present invention can be converted to others by the reaction shown in the following reaction scheme (2). Reaction scheme 2

wherein R ¹ , R ² and A are as defined above, and R ^{1a represents} a different substituent from R ¹ within the same definition range as for R ¹ .

First, connection (1) is through Heat under reflux in one aqueous solution of a Mineral acid, like hydrochloric acid or sulfuric acid, for 5 minutes up to 1 hour in an amine compound (6) converted.

Then the amine compound (6) is acylated. This acylation can be carried out by reacting the amine compound (6) with a carboxylic acid chloride (7) in an amine-based inert solvent such as pyridine, lutidine, triethylamine or 4- (N, N-dimethylamino) pyridine. In this reaction, the carboxylic acid chloride (7) is used in an equimolar amount or more, and the reaction is carried out within about 10 Minutes to 3 hours at a temperature within a range of 0 ° C to room temperature. Since sometimes a compound substituted with a plurality of acyl groups may be included in the acylation reaction, the subject may optionally be heated by refluxing the product together with a catalytic amount of an alkaline agent such as anhydrous potassium carbonate or anhydrous sodium carbonate in an inert solvent, such as methanol or ethanol can be converted into a desired monoacyl compound (8) for about 10 minutes to 2 hours.

Then the so obtained Monoacyl compound (8) by the cyclization reaction into one compound (1a) converted. The cyclization reaction is accomplished by reacting the monoacyl compound (8) with a halogenated trialkylsilane in an inert solvent carried out in the presence of a base.

As the inert solvents, e.g. B. aromatic and aliphatic hydrocarbons, such as toluene, Xylene and petroleum ether; Ethers such as diethyl ether and tetrahydrofuran; and halogenated hydrocarbons, such as dichloromethane, chloroform, Carbon tetrachloride and 1,2-dichloroethane can be used. As the base can preferably z. B. tertiary Amines such as triethylamine, N, N-diethylaniline, N-methylmorpholine, pyridine or 4- (N, N-dimethylamino) pyridine can be used. As the halogenated Trialkylsilanes can preferably z. B. chlorotrialkylsilanes, such as chloromethylsilane, chlorotriethylsilane, Chlorotriethyldimethylsilane, chlorodimethylpropylsilane, chlorobutyldimethylsilane, Chlorotripropylsilane, tributylchlorosilane or chloroethylmethylpropylsilane be used.

The amount of halogenated to use Trialkylsilane and the base is not particularly limited, however it is generally at an equivalent weight or more and preferably 3 to 20 times the equivalent weight based on controls the amount of monoacyl compound (8). The cyclization reaction becomes ordinary within about 0.5 to 30 hours at a temperature within in a range from 0 to 100 ° C completed.

That in every procedure of the reaction scheme desired Object can be easily isolated and cleaned using a conventional release agent become. The release agent closes Adsorption chromatography, preparative thin layer chromatography, Recrystallization, solvent extraction or similar on.

ist, angenommen, daß die Verbindung die folgenden vier Strukturformeln als Tautomer einschließt, und das Tautomer kann durch jede der Strukturformeln dargestellt werden.

worin R¹ und R² wie oben definiert sind.Among the compounds (1) according to the invention prepared as described above, in the case of a compound in which A is a group:

is assumed that the compound includes the following four structural formulas as a tautomer, and the tautomer can be represented by any of the structural formulas.

wherein R ¹ and R ^{2 are} as defined above.

Among the compounds (1) of the present invention, a compound in which R ^{2 is} a styryl group which optionally has 1 to 3 lower alkoxy groups as substituents includes geometric isomers such as E and Z isomers. Any of the two isomers and a mixture thereof can be included in the present invention. In addition, both isomers can be separated using the separating agents described above.

From the compounds according to the invention (1) can pharmaceutically acceptable acid addition salts are formed, and these salts are also in the present invention locked in. The acid that is able to form these salts, e.g. B. inorganic acids, such as Hydrochloric acid, hydrobromic and sulfuric acid; and organic acid like oxalic acid, fumaric acid, maleic acid, Tartaric acid, Citric acid, and p-toluenesulfonic acid on. The acid addition salts can through a conventional Procedures are formed.

From the compounds according to the invention can Alkali metal salts such as sodium salt and potassium salt; alkaline earth such as calcium salt and magnesium salt; and copper salts are formed, and these salts can also be included in the present invention.

The compounds (1) according to the invention are in the form of a general pharmaceutical preparation by using together used with a suitable non-toxic manufacturing vehicle. The manufacturing support conclude Extenders and excipients, such as fillers, extenders, binders, Humectants, disintegrators, surfactants and lubricants, the ordinary according to the form of use of the preparation are used, and these are appropriately selected and according to the unit dosage form of resulting preparation used.

As the unit dosage form of the Pharmaceutical preparation using Compound (1) can take various forms according to the therapeutic Selected for purposes and include typical examples of them, tablets, pills, powders, liquid Preparations, Suspensions, emulsions, granules, Capsules, suppositories, Injections (e.g. liquid Preparations, Suspensions, etc.) and ointments.

In the case of molding into the form of tablets, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silica and potassium phosphate can be used as the production carrier; Binders such as water, ethanol, propanol, simple syrups, gluco se solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose and polyvinyl pyrrolidone; Disintegrators such as sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate and calcium carbonate; Surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate and monoglyceride stearate; Anti-decay agents such as sucrose, stearin, cocoa butter and hydrogenated oil; Absorption accelerators such as quaternary ammonium base and sodium lauryl sulfate; Humectants such as glycerin and starch; Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silica; and lubricants such as purified talc, stearate, powdered and polyethylene glycol can be used.

If necessary, the tablets can be taken in tablets, the one with a common Coating are coated, e.g. B. in sugar-coated tablets, gelatin coated tablets, enteric coated tablets, film-coated tablets, bilayer tablets or multilayer tablets Tablets are shaped.

In the case of molding into the mold of pills can as the manufacturing vehicle, Excipients such as glucose, lactose, boric acid starch, cocoa butter, hardened vegetable oil, kaolin and talk; Binders such as gum arabic, powdered tragacanth, Gelatin and ethanol; and disintegrators such as laminaran and agar be used.

In the case of molding into the mold of suppositories can than the manufacturing vehicles Polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, Gelatin and semi-synthesized glycerides can be used.

Capsules are usually made by Mixing the compound of the invention (1) with various pharmaceutical preparations and filling one hard gelatin capsule or a soft gelatin capsule with the Mixture made.

In the case of making injections, like liquid preparations, Emulsions or suspensions, these are preferably sterilized and are isotonic with blood. In the case of molding into the shape of Injections can as the diluent, Water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated Isostearyl alcohol or polyethylene sorbitan fatty acid esters can be used. In this case you can Contain salt, glucose or glycerin in a sufficient amount to make an isotonic solution and ordinary Solubilizers, buffering agents or soothing agents can also be added.

If necessary, the pharmaceutical preparation further contains Color, preservatives, perfumes, flavorings, sweeteners or other medicines.

In the case of molding into the mold, such as a paste, cream or a gel, can be white soft as the extender Paraffin, paraffin, glycerin, cellulose derivatives, polyethylene glycol, Silicon and bentonite are used.

The amount of the compound of the invention (1) included in the pharmaceutical preparation is not particularly limited and will be expedient selected a wide range but it is preferably within a range of about 1 to 85 % By weight based on the pharmaceutical preparation.

The method of administration of the pharmaceutical preparation is not particularly limited but is appropriate according to the form of the preparation, the age, gender and other conditions of the patients or conditions of the Illness decided. For example, tablets, pills, liquid preparations, suspensions, granule and capsules administered orally while Injections intravenously alone or in combination with a conventional filler, such as Glucose or amino acid, administered, or if necessary, intramuscularly, administered intracutaneously, subcutaneously or intraperitoneally alone. Also be suppository administered intrarectally.

The dose of the pharmaceutical preparation varies dependent the method of administration, age, gender and others states of the patient or conditions of diseases, but a daily dose the compound of the invention (1) is common within a range of about 0.5 to 20 mg / kg and preferred from about 1 to 10 mg / kg. The pharmaceutical preparation can be administered 1 to 4 times a day become.

[Industrial applicability]

It is believed that the triazolopurine derivative of the invention is an antihypertensive or anti-allergic agent, anti-inflammatory agent, remedy for ischemic heart disease, Remedies for leukemia, itching inhibitory agent, expectorant Remedies, cough medicine, remedies for asthma and analgesic due his affinity across from an adenosine A3 receptor is used.

[Examples]

The following reference examples, example, experiments and manufacturing examples illustrate the compounds of the invention in further detail.

Reference example 1

[Production of methyl-N- (5-cyanoimidazol-4-yl) acetimidate]

5 g of 4-amino-5-cyanoimidazole was suspended in 10 ml of DMF, and 10 ml of trimethyl orthoacetate was added, followed by stirring at 90 ° C for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was diluted with ethyl acetate, and then 4.2 g of the desired crystal-separated compound was collected by filtration. The solution was concentrated and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) and then recrystallized from ethyl acetate-n-hexane to obtain 2.9 g of a desired compound as a crystal.
Melting point: 147-149 ° C.

Reference example 2

Methyl-N- (5-cyanoimidazol-4-yl) pentanimidate was prepared in the same manner as in Reference Example 1.
Melting point: 114-116 ° C.

Reference example 3

Methyl-N- (5-cyanoimidazol-4-yl) benzimidate was prepared in the same manner as in Reference Example 1.
Melting point: 157-159 ° C.

• – Methyl-N-(5-cyanoimidazol-4-yl)propionimidat,
• – Methyl-N-(5-cyanoimidazol-4-yl)butyrimidat,
• – Methyl-N-(5-cyanoimidazol-4-yl)hexanimidat,
• – Methyl-N-(5-cyanoimidazol-4-yl)heptanimidat,
• – Methyl-N-(5-cyanoimidazol-4-yl)octanimidat,
• – Methyl-N-(5-cyanoimidazol-4-yl)nonanimidat,
• – Methyl-N-(5-cyanoimidazol-4-yl)-3-methylbenzimidat.

In the same manner as in Reference Example 1, the following compounds could be produced.

• Methyl N- (5-cyanoimidazol-4-yl) propionimidate,
• Methyl N- (5-cyanoimidazol-4-yl) butyrimidate,
• Methyl N- (5-cyanoimidazol-4-yl) hexanimidate,
• Methyl N- (5-cyanoimidazol-4-yl) heptanimidate,
• Methyl N- (5-cyanoimidazol-4-yl) octanimidate,
• Methyl N- (5-cyanoimidazol-4-yl) nonanimidate,
• - Methyl-N- (5-cyanoimidazol-4-yl) -3-methylbenzimidate.

Reference example 4

• – Methyl-N-(1-benzyl-4-cyanoimidazol-5-yl)acetimidat,
• – Methyl-N-(1-benzyl-4-cyanoimidazol-5-yl)propionimidat,
• – Methyl-N-(1-benzyl-4-cyanoimidazol-5-yl)butyrimidat,
• – Methyl-N-(1-benzyl-4-cyanoimidazol-5-yl)pentanimidat,
• – Methyl-N-(1-benzyl-4-cyanoimidazol-5-yl)hexanimidat,
• – Methyl-N-(1-benzyl-4-cyanoimidazol-5-yl)heptanimidat,
• – Methyl-N-(1-benzyl-4-cyanoimidazol-5-yl)octanimidat,
• – Methyl-N-(1-benzyl-4-cyanoimidazol-5-yl)nonanimidat,
• – Methyl-N-(1-benzyl-4-cyanoimidazol-5-yl)benzimidat,
• – Methyl-N-(1-benzyl-4-cyanoimidazol-5-yl)-3-methylbenzimidat.

In the same manner as in Reference Example 1, except that 5-amino-1-benzyl-4-cyanoimidazole was used as the starting material, the following corresponding compounds could be prepared.

• Methyl N- (1-benzyl-4-cyanoimidazol-5-yl) acetimidate,
• Methyl N- (1-benzyl-4-cyanoimidazol-5-yl) propionimidate,
• Methyl N- (1-benzyl-4-cyanoimidazol-5-yl) butyrimidate,
• Methyl N- (1-benzyl-4-cyanoimidazol-5-yl) pentanimidate,
• Methyl N- (1-benzyl-4-cyanoimidazol-5-yl) hexanimidate,
• Methyl N- (1-benzyl-4-cyanoimidazol-5-yl) heptanimidate,
• Methyl N- (1-benzyl-4-cyanoimidazol-5-yl) octanimidate,
• Methyl N- (1-benzyl-4-cyanoimidazol-5-yl) nonanimidate,
• Methyl N- (1-benzyl-4-cyanoimidazol-5-yl) benzimidate,
• - Methyl-N- (1-benzyl-4-cyanoimidazol-5-yl) -3-methylbenzimidate.

Reference example 5

• – Methyl-N-(1-benzyl-5-cyanoimidazol-4-yl)heptanimidat,
• – Methyl-N-(5-cyano-1-methylimidazol-4-yl)heptanimidat,
• – Methyl-N-(4-cyano-1-methylimidazol-5-yl)heptanimidat,
• – Methyl-N-(5-cyano-1-ethylimidazol-4-yl)heptanimidat,
• – Methyl-N-(4-cyano-1-ethylimidazol-5-yl)heptanimidat,

In the same manner as in Reference Example 1, except that 4-amino-1-benzyl-5-cyanoimidazole, 5-amino-4-cyano-1-methylimidazole, 4-amino-5-cyano-1-methylimidazole, 5-amino -4-cyano-1-ethylimidazole and 4-amino-5-cyano-1-ethylimidazole were used as starting materials, the following corresponding compounds were prepared.

• Methyl N- (1-benzyl-5-cyanoimidazol-4-yl) heptanimidate,
• Methyl N- (5-cyano-1-methylimidazol-4-yl) heptanimidate,
• Methyl N- (4-cyano-1-methylimidazol-5-yl) heptanimidate,
• Methyl N- (5-cyano-1-ethylimidazol-4-yl) heptanimidate,
• Methyl N- (4-cyano-1-ethylimidazol-5-yl) heptanimidate,

example 1

[Preparation of 5-methyl-8-phenyl-1H-1,2,4-triazolo [5,1-i] purine

4.0 g obtained in Reference Example 1 Methyl-N- (5-cyanoimidazol-4-yl) acetimidate and 3.65 g of N-benzoylhydrazine were dissolved in 40 ml of DMF, followed stirring for an hour at 80 ° C and further stirring for 15 hours at 150 ° C. The reaction solution was air cooled to room temperature, and the pH of the solution was within a range of 9-10 by dropwise Add 13 ml of an aqueous 10% solution Sodium hydroxide solution set, followed by stirring for one hour at room temperature. To At the end of the reaction, 10% hydrochloric acid and water were alternated added to thereby adjust the pH to 3. The secluded Crystals were collected by filtration and with hot ethanol washed to 5.5 g of a desired To get compound as a crystal. The structure and melting point the resulting desired Compound are shown in Table 9.

Examples 2 to 20

In the same way as in example 1, except that a the corresponding in the reference examples described above 1 to 3 compounds obtained and a predetermined acyl derivative used were the corresponding connections with that in tables 9 and 10 structures and melting points shown. In Tables 9 and 10 denotes Me a methyl group, n-Bu denotes an n-butyl group or Ph denotes a phenyl group.

Table 9

Table 10

The measurement results of the NMR of the resulting corresponding connections are shown below.

Connection of example 1

• ¹ H NMR (DMSO-d ₆ ) δ: 3.03 (3H, s), 7.5-7.7 (3H, m), 8.3-8.4 (2H, m), 8.48 (1H, s), 13.6-14.1 (1H, brs).

Connection of example 2

• ¹ H-NMR (DMSO-d ₆ ) δ: 2.98 (3H, s), 3.76 (3H, s), 3.92 (6H, s), 7.56 (2H, s), 8, 42 (1H, s), 13.6-14.1 (1H, brs).

Connection of example 3

• ¹ H NMR (DMSO-d ₆ ) δdd: 3.05 (3H, s), 7.69 (1H, J = 4.9, 7.9), 8.50 (1H, s), 8, 65 (1H, d, J = 7.9), 8.81 (1H, d, J = 4.9), 9.49 (1H, s), 13.5-14.1 (1H, brs).

Connection of example 4

• ¹ H NMR (DMSO-d ₆ ) δ: 1.05 (3H, t, J = 7.4), 1.5-1.6 (2H, m), 1.9-2.1 (2H, m), 3.43 (2H, t, J = 7.4), 7.6-7.7 (3H, m), 8.3-8.4 (2H, m), 8.50 (1H, s), 13.6-14.2 (1H, brs).

Connection of example 5

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.4), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 2.40 (3H, s), 3.35 (2H, t, J = 7.4), 7.38 (2H, d, J = 7.9), 8.16 (2H, d, J = 7.9), 8.42 (1H, s), 13.5-14.0 (1H, brs).

Connection of example 6

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 3.36 (2H, t, J = 7.7), 7.0-7.1 (2H, m), 7.42 (1H, t, J = 8.2), 8.17 ( 1H, d, J = 7.9), 8.48 (1H, s), 11.21 (1H, s), 13.7-14.1 (1H, brs).

Connection of example 7

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.4), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.34 (2H, t, J = 6.9), 6.94 (2H, d, J = 8.9), 8.11 (2H, d, J = 8.9), 8, 40 (1H, s), 9.7-10.2 (1H, brs), 13.3-14.2 (1H, brs).

Connection of example 8th

• ¹ H NMR (DMSO-d ₆ ) δ: 1.04 (3H, t, J = 7.4), 1.4-1.6 (2H, m), 1.9-2.1 (2H, m), 3.37 (2H, t, J = 7.4), 3.92 (3H, s), 7.17 (2H, d, J = 7.9), 8.17 (1H, s) , 8.27 (2H, d, J = 7.9).

Connection of example 9

• ¹ H NMR (DMSO-d ₆ ) δ: 0.96 (3H, t, J = 7.4), 1.4-1.5 (2H, m), 1.9-2.0 (2H, m), 3.36 (2H, t, J = 7.5), 7.5-7.7 (3H, m), 8.0-8.2 (1H, m), 8.47 (1H, s).

Connection of example 10

• ¹ H NMR (DMSO-d ₆ ) δ: 0.96 (3H, t, J = 6.9), 1.4-1.5 (2H, m), 1.8-2.0 (2H, m), 3.30 (2H, t, J = 7.4), 7.81 (1H, t, J = 7.9), 7.89 (1H, t, J = 7.9), 8, 03 (1H, d, J = 7.9), 8.21 (1H, d, J = 7.9), 8.46 (1H, s), 13.7-14.1 (1H, brs).

Connection of example 11

• ¹ H NMR (DMSO-d ₆ ) δ: 0.99 (3H, t, J = 6.9), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 3.33 (2H, t, J = 7.9), 8.37 (2H, d, J = 8.9), 8.43 (1H, s), 8.45 (2H, d, J = 8.9).

Connection of example 12

• ¹ H NMR (DMSO-d ₆ ) δ: 1.04 (3H, t, J = 7.4), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m), 3.48 (2H, t, J = 7.4), 3.95 (3H, s), 4.00 (6H, s), 7.65 (2H, s), 8.19 (1H , s).

Connection of example 13

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.4), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 3.38 (2H, t, J = 7.4), 7.62 (1H, dd, J = 5.0, 7.9), 8.44 (1H, s), 8.59 ( 1H, d, J = 7.9), 8.75 (1H, d, J = 5.0), 9.42 (1H, s).

Connection of example 14

• ¹ H NMR (DMSO-d ₆ ) δ: 0.99 (3H, t, J = 6.9), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.38 (2H, t, J = 7.4), 8.18 (2H, d, J = 5.9), 8.46 (1H, s), 8.81 (2H, d, J = 5.9).

Connection of example 15

• ¹ H NMR (DMSO-d ₆ ) δ: 0.97 (3H, t, J = 7.4), 1.4-1.5 (2H, m), 1.8-2.0 (2H, m), 3.33 (2H, t, J = 7.4), 6.75 (1H, dd, J = 2.0, 3.5), 7.29 (1H, brd, J = 3.5 ), 7.97 (1H, brs), 8.43 (1H, s), 13.6-14.0 (1H, brs).

Connection of example 16

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 6.9), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 3.32 (2H, t, J = 7.4), 7.27 (1H, dd, J = 3.5, 4.9), 7.80 (1H, dd, J = 1.0 , 4.9), 7.92 (1H, dd, J = 1.0, 3.5), 8.43 (1H, s), 13.5-14.1 (1H, brs).

Connection of example 17

• ¹ H NMR (DMSO-d ₆ ) δ: 0.96 (3H, t, J = 7.4), 1.4-1.5 (2H, m), 1.8-2.0 (2H, m), 3.30 (2H, t, J = 7.8), 7.3-7.5 (4H, m), 7.7-7.8 (2H, m), 7.87 (1H, d, J = 16.3), 8.41 (1H, s), 13.5-14.0 (1H, brs).

Connection of example 18

• ¹ H NMR (DMSO-d ₆ ) δ: 7.5-7.6 (3H, m), 7.6-7.7 (3H, m), 8.2-8.3 (2H, m) , 8.4-8.5 (2H, m), 8.54 (1H, s), 13.7-14.2 (1H, brs).

Connection of example 19

• ¹ H NMR (DMSO-d ₆ ) δ: 3.84 (3H, s), 3.97 (6H, s), 7.59 (2H, s), 7.7-7.8 (3H, m ), 8.5-8.6 (2H, m), 8.58 (1H, s).

Connection of example 20

• ¹ H NMR (DMSO-d ₆ ) δ: 7.6-7.7 (4H, m), 8.5-8.6 (4H, m), 8.7-8.8 (1H, m) , 9.43 (1H, s).

Examples 21 to 33 and 38 to 40

In the same way as in example 1, except that a the corresponding in the reference examples described above 1 to 4 compounds obtained and a predetermined acylhydrazine derivative were used, the corresponding connections with the structures and melting points shown in Tables 11 and 12.

Example 34

Preparation of 5-pentyl-8-phenyl-1H-1,2,4-triazolo [5,1-i] purine

4.4 g of those obtained in Example 1 Connection became a solution of 20 ml of concentrated hydrochloric acid added to 50 ml of water, and then the solution was refluxed for 30 minutes heated. The reaction solution was cooled to room temperature, and aqueous 25% Ammonia was added to adjust the pH to 8. The secluded Crystals were collected by filtration and from 75% ethanol recrystallized to 2.58 g of 3- (4-aminopyrazol-5-yl) -5-phenyl-1,2,4-triazole To get crystal.

2 g of the crystal thus obtained were dissolved in 20 ml of pyridine and 4.16 g of hexanoyl chloride were added dropwise at 0 ° C. followed by stirring for 30 minutes at 0 ° C and stirring for a further 30 minutes at room temperature. The reaction solution was washed with ethyl acetate diluted alternating with aqueous citric acid, aqueous sodium hydrogen carbonate and more saturated saline solution washed, over dried anhydrous magnesium sulfate, and then under reduced Pressure dried. The residue was by silica gel column chromatography (The eluent was chloroform and then a mixture of chloroform and methanol (30: 1) used). cleaned to 5 g of an oily substance to obtain. This oily Substance was dissolved in 40 ml of ethanol and 10 mg of anhydrous Potassium carbonate was added, followed by heating under for 30 minutes Reflux. To Cool the reaction solution The deposited crystals were brought to room temperature by filtration collected, washed with ethanol and dried to give 1.9 g of 3- [4- (N-hexanoylamino) pyrazol-5-yl] -5-phenyl-1,2,4-triazole to get as a crystal.

Then 0.4 g of the thus obtained was Crystal suspended in 8 ml of tetrahydrofuran, and 1.77 ml of triethylamine and 0.63 ml of chlorotrimethylsilane were added, followed by 20 Hours of heating under reflux. To End of the reaction, ice water and 2 g of citric acid were alternately added, and the reaction solution was extracted with ethyl acetate. The organic layer was collected, washed alternately with water and saturated saline, over anhydrous Magnesium sulfate dried and then concentrated under reduced pressure. The residue was by silica gel column chromatography (The eluent was chloroform and then a mixture of chloroform and methanol (25: 1 used)), and from methanol-water recrystallized to 0.15 g of a desired compound as a To get crystal. The structure and melting point of the resulting desired Compound are shown in Table 12.

Examples 35 to 37

In the same way as in example 34 were the corresponding compounds with the in Table 12 structures and melting points shown.

Denoted in Tables 11 and 12 Me denotes a methyl group, Et denotes an ethyl group, n-Pr denotes an n-propyl group, n-Bu denotes an n-butyl group, n-Pe denotes an n-pentyl group, n-Hx denotes an n-hexyl group, n-Hp denotes an n-heptyl group, Ph denotes a phenyl group and Bn denotes a benzyl group.

Table 11

Table 12

The results of the NMR of the resulting corresponding connections are shown below.

Connection of example 21

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 6.9), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 3.35 (2H, t, J = 7.4), 7.64 (2H, d, J = 8.4), 8.27 (2H, d, J = 8.4), 8, 43 (1H, s), 13.6-14.0 (1H, s, brs).

Connection of example 22

• ¹ H NMR (DMSO-d ₆ ) δ: 1.46 (3H, t, J = 7.4), 3.39 (2H, q, J = 7.4), 7.5-7.7 ( 3H, m), 8.2-8.3 (2H, m), 8.43 (1H, s), 13.6-14.0 (1H, brs).

Connection of example 23

• ¹ H NMR (DMSO-d ₆ ) δ: 1.07 (3H, t, J = 7.4), 1.9-2.1 (2H, m), 3.33 (2H, t, J = 7.7), 7.5-7.7 (3H, m), 8.2-8.3 (2H, m), 8.43 (1H, s).

Connection of example 24

• ¹ H NMR (DMSO-d ₆ ) δ: 1.46 (3H, t, J = 7.4), 3.40 (2H, q, J = 7.4), 3.76 (3H, s) , 3.92 (6H, s), 7.56 (2H, s), 8.43 (1H, s), 13.6-14.0 (1H, brs).

Connection of example 25

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 3.34 (2H, t, J = 7.7), 7.6-7.7 (2H, m), 8.2-8.3 (2H, m), 8.43 (1H, s).

Connection of example 26

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.36 (2H, t, J = 7.9), 3.88 (3H, s), 7.12 (1H, d, J = 8.4), 7.49 (1H, dd, J = 7.7, 8.4), 7.79 (1H, s), 7.86 (1H, d, J = 7.7), 8.43 (1H, s), 13.6-14, 0 (1H, brs).

Connection of example 27

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.4), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 3.34 (2H, t, J = 7.4), 3.86 (3H, s), 7.11 (2H, d, J = 8.9), 8.20 (2H, d, J = 8.9), 8.41 (1H, s).

Connection of example 28

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 2.43 (3H, s), 3.34 (2H, t, J = 7.7), 7.35 (1H, d, J = 7.7), 7.45 (1H, t, J = 7.7), 8.07 (1H, d, J = 7.7), 8.08 (1H, s), 8.42 (1H, s), 13.5-14.0 (1H, brs).

Connection of example 29

• ¹ H NMR (DMSO-d ₆ ) δ: 0.95 (3H, t, J = 7.2), 1.3-1.5 (2H, m), 1.8-2.0 (2H, m), 2.54 (3H, s), 3.25 (2H, t, J = 7.9), 8.38 (1H, s).

Connection of example 30

• ¹ H NMR (DMSO-d ₆ ) δ: 0.95 (3H, t, J = 7.2), 1.3-1.5 (2H, m), 1.8-2.0 (2H, m), 3.28 (2H, t, J = 7.9), 4.25 (2H, s), 7.2-7.5 (5H, m), 8.38 (1H, s).

Connection of example 31

• ¹ H NMR (DMSO-d ₆ ) δ: 0.96 (3H, t, J = 7.4), 1.3-1.6 (2H, m), 1.8-2.0 (2H, m), 3.29 (3H, t, J = 7.4), 3.71 (3H, s), 3.87 (6H, s), 7.13 (2H, s), 7.46 (1H , d, J = 16.3), 7.81 (1H, d, J = 16.3), 8.41 (1H, s), 13.5-14.0 (1H, brs).

Connection of example 32

• ¹ H NMR (DMSO-d ₆ ) δ: 0.94 (3H, t, J = 7.2), 1.4-1.5 (2H, m), 1.8-2.0 (2H, m), 3.0-3.4 (6H, m), 3.61 (3H, s), 3.73 (6H, s), 6.61 (2H, s), 8.39 (1H, s ).

Connection of example 33

• ¹ H NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.2), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m) , 3.44 (2H, t, J = 7.4), 5.78 (2H, s), 7.3-7.4 (3H, m), 7.5-7.6 (5H, m) , 8.04 (1H, s), 8.3-8.4 (2H, m).

Connection of example 34

• ¹ H NMR (DMSO-d ₆ ) δ: 0.91 (3H, t, J = 6.9), 1.3-1.5 (4H, m), 1.9-2.0 (2H, m), 3.36 (2H, t, J = 7.4), 7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.43 (1H, s).

Connection of example 35

• ¹ H NMR (DMSO-d ₆ ) δ: 2.49 (3H, s), 7.4-7.6 (5H, m), 8.2-8.4 (4H, m), 8.54 (1H, s).

Connection of example 36

• ¹ H NMR (DMSO-d ₆ ) δ: 0.88 (3H, t, J = 7.2), 1.2-1.6 (6H, m), 1.9-2.0 (2H, m), 3.36 (2H, t, J = 7.7), 7.4-7.7 (3H, m), 8.2-8.3 (2H, m), 8.43 (1H, s), 13.6-14.1 (1H, brs).

Connection of example 37

• ¹ H NMR (DMSO-d ₆ ) δ: 0.86 (3H, t, J = 6.9), 1.2-1.5 (8H, m), 1.8-2.0 (2H, m), 3.34 (2H, t, J = 7.9), 7.5-7.6 (3H, m), 8.2-8.3 (2H, m), 8.43 (1H, s).

Connection of example 38

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.4), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.36 (2H, t, J = 7.7), 7.41 (2H, t, J = 8.9), 8.31 (2H, dd, J = 6.4, 8.9 ), 8.43 (1H, s).

Connection of example 39

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.4), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.35 (2H, t, J = 7.4), 7.78 (2H, d, J = 8.4), 8.21 (2H, d, J = 8.4), 8, 43 (1H, s).

Connection of example 40

¹ H NMR (DMSO-d ₆ ) δ: 1.04 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.9-2.1 (2H, m), 3.39 (2H, t, J = 7.2), 5.70 (2H, s), 6.76 (2H, d, J = 8.7), 8.02 (2H, d, J = 8.7), 8.44 (1H, s).

Examples 41 to 73

In the same way as in example 1, except that a the corresponding in the reference examples described above 1 to 5 compounds obtained, a predetermined acylhydrazine derivative was used, the corresponding compounds with the in Table 13 to 15 structures and melting points shown.

Denoted in Tables 13 to 15 Me denotes a methyl group, Et denotes an ethyl group, n-Pr denotes an n-propyl group, i-Pr denotes an isopropyl group, n-Bu denotes an n-butyl group, t-Bu denotes a t-butyl group, n-Pe denotes an n-pentyl group, Ph denotes a phenyl group or Bn denotes a benzyl group.

Table 13

Table 14

Table 15

The measurement results of the NMR of the NMR the resulting corresponding compounds are shown below.

Connection of example 41

• ¹ H NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.2), 1.5-1.6 (2H, m), 1.9-2.1 (2H, m) , 3.45 (2H, t, J = 7.4), 5.49 (2H, s), 7.3-7.4 (5H, m), 7.5-7.6 (3H, m) , 7.97 (1H, s), 8.4-8.5 (2H, m).

Connection of example 42

• ¹ H NMR (DMSO-d ₆ ) δ: 1.04 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.9-2.1 (2H, m), 3.07 (6H, s), 3.40 (2H, t, J = 7.4), 6.91 (2H, d, J = 8.7), 8.15 (2H, d, J = 8.7), 8.45 (1H, s).

Connection of example 43

• ¹ H NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.2), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m) , 3.44 (2H, t, J = 7.4), 4.30 (3H, s), 7.5-7.6 (3H, m), 7.99 (1H, s), 8.3 - 8.4 (2H, m).

Connection of example 44

• ¹ H NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.4), 1.5-1.6 (2H, m), 2.0-2.1 (2H, m) , 3.45 (2H, t, J = 7.4), 3.97 (3H, s), 7.5-7.6 (3H, m), 7.97 (1H, s), 8.4 - 8.5 (2H, m).

Connection of example 45

• ¹ H NMR (DMSO-d ₆ ) δ: 0.9-1.1 (6H, m), 1.4-1.6 (2H, m), 1.7-1.8 (2H, m) , 1.9-2.0 (2H, m), 3.34 (2H, t, J = 7.7), 4.02 (2H, t, J = 6.4), 7.11 (2H, d, J = 8.4), 8.19 (2H, d, J = 8.4), 8.41 (1H, s).

Connection of example 46

• ¹ H NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.4), 1.5-1.6 (2H, m), 1.74 (3H, t, J = 7, 4), 2.0-2.1 (2H, m), 3.44 (2H, t, J = 7.7), 4.63 (2H, q, J = 7.4), 7.5- 7.6 (3H, m), 8.04 (1H, s), 8.3-8.4 (2H, m).

Connection of example 47

• ¹ H NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.4), 1.5-1.6 (2H, m), 1.61 (3H, t, J = 7, 4), 1.9-2.1 (2H, m), 3.44 (2H, t, J = 7.4), 4.39 (2H, q, J = 7.4), 7.4- 7.6 (3H, m), 8.00 (1H, s), 8.4-8.5 (2H, m).

Connection of example 48

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.38 (3H, t, J = 6.9), 1.4-1.6 ( 2H, m), 1.9-2.0 (2H, m), 3.34 (2H, t, J = 7.4), 4.12 (2H, q, J = 6.9), 7, 09 (2H, d, J = 8.7), 8.19 (2H, d, J = 8.7), 8.41 (1H, s).

Connection of example 49

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 6.9), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 3.34 (2H, t, J = 7.4), 5.20 (2H, s), 7.20 (2H, d, J = 8.9), 7.3-7.5 ( 5H, m), 8.21 (2H, d, J = 8.9), 8.41 (1H, s).

Connection of example 50

• ¹ H NMR (DMSO-d ₆ ) δ: 0.99 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 3.38 (2H, t, J = 7.7), 7.3-7.6 (3H, m), 7.78 (2H, d, J = 8.2), 7.89 ( 2H, d, J = 7.7), 8.36 (2H, d, J = 7.7), 8.43 (1H, s).

Connection of example 51

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.36 (2H, t, J = 6.9), 3.86 (3H, s), 3.90 (3H, s), 7.15 (1H, d, J = 8.2) , 7.78 (1H, s), 7.86 (1H, d, J = 8.2), 8.41 (1H, s).

Connection of example 52

• ¹ H NMR (DMSO-d ₆ ) δ: 0.96 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.9-2.1 (2H, m), 3.35 (2H, t, J = 7.4), 7.65 (1H, dd, J = 2.0, 8.4), 7.86 (1H, d, J = 2.0 ), 8.15 (1H, d, J = 8.4), 8.45 (1H, s).

Connection of example 53

• ¹ H NMR (DMSO-d ₆ ) δ: 0.95 (3H, t, J = 7.4), 1.5-1.6 (2H, m), 1.8-2.0 (2H, m), 3.28 (2H, t, J = 7.4), 3.72 (3H, s), 3.73 (3H, s), 4.18 (2H, s), 6.89 (2H , s), 7.01 (1H, s), 8.37 (1H, s).

Connection of example 54

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.15 (6H, t, J = 6.9), 1.4-1.6 ( 2H, m), 1.9-2.0 (2H, m), 3.33 (2H, t, J = 7.4), 3.42 (4H, q, J = 6.9), 6.80 (2H, d, J = 8.9), 8.06 (2H, d, J = 8.9 ), 8.38 (1H, s).

Connection of example 55

• ¹ H NMR (DMSO-d ₆ ) δ: 0.97 (3H, t, J = 6.9), 1.20 (3H, t, J = 6.9), 1.4-1.5 ( 2H, m), 1.8-2.0 (2H, m), 3.0-3.2 (2H, m), 3.32 (2H, t, J = 7.9), 6.13 ( 1H, brs), 6.69 (2H, d, J = 7.4), 8.00 (2H, d, J = 7.4), 8.38 (1H, s), 13.5-13, 9 (1H, brs).

Connection of example 56

• ¹ H NMR (DMSO-d ₆ ) δ: 0.9-1.0 (6H, m), 1.4-1.6 (4H, m), 1.7-1.8 (2H, m) , 1.8-2.0 (2H, m), 3.35 (2H, t, J = 7.4), 4.07 (2H, t, J = 6.4), 7.11 (2H, d, J = 8.9), 8.20 (2H, d, J = 8.9), 8.40 (1H, s), 13.5-14.0 (1H, brs).

Connection of example 57

• ¹ H NMR (DMSO-d ₆ ) δ: 0.91 (3H, t, J = 6.9). 0.98 (3H, t, J = 7.4), 1.3-1.6 (6H, m), 1.7-1.8 (2H, m), 1.8-2.0 (2H , m), 3.34 (2H, t, J = 7.4), 4.05 (2H, t, J = 6.4), 7.10 (2H, d, J = 8.9), 8 , 19 (2H, d, J = 8.9), 8.41 (1H, s), 13.5-14.0 (1H, brs).

Connection of example 58

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.4), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.36 (2H, t, J = 7.4), 7.58 (2H, d, J = 8.6), 8.39 (2H, d, J = 8.6), 8, 44 (1H, s), 13.6-14.0 (1H, brs).

Connection of example 59

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 3.33 (2H, t, J = 7.7), 7.92 (2H, d, J = 7.9), 8.43 (1H, s), 8.44 (2H, d, J = 7.9).

Connection of example 60

• ¹ H NMR (DMSO-d ₆ ) δ: 0.95 (3H, t, J = 7.2), 1.3-1.5 (2H, m), 1.8-2.0 (2H, m), 3.30 (2H, t, J = 7.7), 4.80 (4H, s), 6.85 (2H, d, J = 8.4), 7.2-7.4 ( 10H, m), 8.00 (2H, d, J = 8.4), 8.37 (1H, s).

Connection of example 61

• ¹ H NMR (DMSO-d ₆ ) δ: 0.97 (3H, t, J = 7.2), 1.3-1.5 (2H, m), 1.8-2.0 (2H, m), 3.31 (2H, t, J = 7.4), 4.37 (2H, d, J = 5.9), 6.74 (2H, d, J = 8.7), 6, 82 (1H, t, J = 5.9), 7.2-7.4 (5H, m), 7.98 (2H, d, J = 8.7), 8.38 (1H, s), 13.5-14.0 (1H, brs).

Connection of example 62

• ¹ H NMR (DMSO-d ₆ ) δ: 0.97 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 3.35 (2H, t, J = 7.4), 7.0-7.3 (5H, m), 7.46 (2H, t, J = 7.4), 8.27 ( 2H, d, J = 7.7), 8.42 (1H, s).

Connection of example 63

• ¹ H NMR (DMSO-d ₆ ) δ: 0.97 (3H, t, J = 7.4), 1.4-1.6 (2H, m), 1.8-2.0 (2H, m), 2.76 (3H, d, J = 5.0), 3.32 (2H, t, J = 7.4), 6.22 (1H, d, J = 5.0), 6, 68 (2H, d, J = 8.4), 8.02 (2H, d, J = 8.4), 8.38 (1H, s), 13.5-14.0 (1H, brs).

Connection of example 64

• ¹ H NMR (DMSO-d ₆ ) δ: 1.00 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.40 (2H, t, J = 7.7), 7.5-7.7 (2H, m), 8.0-8.1 (1H, m), 8.10 (1H, d, J = 8.4), 8.1-8.2 (1H, m), 8.37 (1H, d, J = 8.4), 8.44 (1H, s), 8.88 ( 1H, s).

Connection of example 65

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.1-1.2 (6H, m), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.2-3.4 (4H, m), 3.9-4.1 (4H, m), 7.48 (2H, d, J = 7.9), 8.22 (2H, d, J = 7.9), 8.43 (1H, s), 13.6-14.0 (1H, brs).

Connection of example 66

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 2.56 (3H, s), 3.35 (2H, t, J = 7.4), 7.44 (2H, d, J = 8.7), 8.19 (2H, d, J = 8.7), 8.41 (1H, s).

Connection of example 67

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.24 (3H, t, J = 7.4), 1.4-1.6 ( 2H, m), 1.9-2.0 (2H, m), 2.70 (2H, q, J = 7.4), 3.35 (2H, t, J = 7.9), 7, 41 (2H, d, J = 7.9), 8.19 (2H, d, J = 7.9), 8.42 (1H, s).

Connection of example 68

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.4), 1.26 (6H, d, J = 6.9), 1.4-1.6 ( 2H, m), 1.9-2.0 (2H, m), 2.99 (1H, quintet, J = 6.9), 3.36 (2H, t, J = 7.4), 7, 44 (2H, d, J = 7.9), 8.20 (2H, d, J = 7.9), 8.42 (1H, s).

Connection of example 69

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.35 (9H, s), 1.4-1.5 (2H, m), 1 , 9-2.0 (2H, m), 3.36 (2H, t, J = 7.7), 7.60 (2H, d, J = 8.2), 8.21 (2H, d, J = 8.2), 8.42 (1H, s).

Connection of example 70

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 6.9), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.35 (2H, t, J = 6.9), 3.36 (3H, s), 4.51 (2H, s), 7.50 (2H, d, J = 8.4) , 8.25 (2H, d, J = 8.4), 8.42 (1H, s).

Connection of example 71

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.38 (2H, t, J = 7.7), 4.60 (2H, s), 4.64 (2H, s), 7.2-7.4 (5H, m), 7 , 56 (2H, d, J = 8.2), 8.28 (2H, d, J = 8.2), 8.42 (1H, s), 13.6-14.0 (1H, brs) ,

Connection of example 72

• ¹ H NMR (DMSO-d ₆ ) δ: 0.98 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.36 (2H, t, J = 8.2), 7.11 (1H, dd, J = 2.0, 8.4), 7.16 (1H, d, J = 2.0 ), 8.16 (1H, d, J = 8.4), 8.49 (1H, s), 11.49 (1H, brs).

Connection of example 73

• ¹ H NMR (DMSO-d ₆ ) δ: 1.00 (3H, t, J = 7.2), 1.4-1.6 (2H, m), 1.9-2.0 (2H, m), 3.42 (2H, t, J = 7.7), 7.3-7.6 (3H, m), 7.79 (1H, d, J = 7.9), 8.03 ( 1H, d, J = 8.7), 8.50 (1H, s), 8.83 (1H, s), 11.14 (1H, brs), 13.7-14.1 (1H, brs) ,

experiment

[Adenosine A3 receptor binding ability test Triazolopurine derivative (1)]

According to that in Molecular Pharmacology, 45, 978 (1994) a test of the adenosine A3 receptor binding ability was carried out.

A cell membrane of human renal endothelial cells HEK-293 transformed with a plasmid encoding an adenosine A3 receptor was isolated in a tris-hydrochloric acid buffer (pH 7.7) according to a conventional method, and then the cell membrane was ¹²⁵ I-labeled N ⁶ - (4-aminobenzyl) -9- [5- (methylcarbonyl) -β-dribofuranosyl] adenine (AB-MECA) treated to produce a cell membrane to which the compound is bound.

Then this cell membrane and a test compound were incubated and the amount of [ ¹²⁵ I] AB-MECA released was measured. The concentration of the test compound when 50% of the [ ¹²⁵ I] AB-MECA, IC ₅₀ , was released was determined from the measured value of the test compound at each concentration.

The adenosine A1 receptor binding capacity and the adenosine A2 receptor binding capacity of the test compound were measured according to the method described in Archives of Pharmacology, 336, 204 (1987) and The Journal of Pharmacology and Experimental Therapeutics, 251 (3), 888 (1988) and then rated as IC ₅₀ .

The measurement results are in the following Tables shown.

Table 16

Table 17

As obvious from the tables the compounds of the invention an affinity across from the adenosine A3 receptor and their selectivity is high.

Production Example 1

(Manufacture of tablets)

2000 tablets, each containing 300 mg of the compound obtained in Example 1 (5-methyl-8-phenyl-1H-1,2,4-triazolo [5,1-i] purine) as an active ingredient, were made according to the following formulation manufactured: Compound obtained in Example 1 600 g Lactose (Japanese pharmacopoeia) 67 g Corn Starch (Japanese Pharmacopoeia) 33 g Calcium carboxymethyl cellulose (Japanese pharmacopoeia) 25 g Methyl cellulose (Japanese pharmacopoeia) 12 g Magnesium stearate (Japanese pharmacopoeia) 3 g

According to the formulation described above, desired tablets were obtained by sufficiently mixing the compound obtained in Example 1, lactose, corn starch and calcium carboxymethyl cellulose, granulating the resulting mixture using an aqueous methyl cellulose, passing through the granules obtained through a # 24 mesh sieve, mixing the granules with magnesium stearate and compressing the mixture into tablets.

Production Example 2

(Manufacture of capsules)

2000 hard gelatin capsules, each 200 mg of the compound obtained in Example 12 (5-n-butyl-8- (3,4,5-trimethoxyphenyl) -1H-1,2,4-triazolo [5,1-i] purine ) contains as active ingredient, were prepared according to the following formulation. Compound obtained in Example 12 400 g Crystalline cellulose (Japanese pharmacopoeia) 60 g Corn Starch (Japanese Pharmacopoeia) 34 g Talk (Japanese Pharmacopoeia) 4 g Magnesium stearate (Japanese pharmacopoeia) 2 g

According to the formulation described above were desired Capsules by pulverizing the appropriate ingredients to Powder form, mixing the powder to make an even mix to get and fill a gelatin capsule for oral administration with a desired one Size with the Get mixture.

Claims (11)

Triazolopurine derivative represented by the general formula (1):

wherein R ^{1 represents} an alkyl group or a phenyl group which is optionally substituted with a C _1-6 alkyl group; R ^{2 represents} a pyridyl group, a furyl group, a thienyl group, a C _1-6 alkyl group, a phenyl C _1-6 alkyl group which optionally has 1 to 3 C _1-6 alkoxy groups as substituents, a styryl group, which optionally has 1 to 3 C _1-6 alkoxy groups as substituents, a naphthyl group which optionally has a hydroxy group as substituents, or a phenyl group which optionally has 1 to 3 groups as substituents selected from a C _1-6 alkyl group, C _1-6 alkoxy group, nitro group, hydroxy group, amino group, NC _1-6 alkylamino group, N, N-di-C _1-6 alkylamino group, N-phenyl-C _1-6 alkylamino group, N, N-bisphenyl-C _1-6 alkylamino group, phenyl group, phenoxy group, phenyl-C _1-6 alkoxy group, halogen-substituted C _1-6 alkyl group, halogen-substituted C _1-6 alkoxy group, di- C _1-6 -alkylphosphorylmethyl group, C _1-6 alkylthio, C _1-6 alkoxy-C _1-6 alkyl group, phenyl-C _1-6 -alkoxy-C _1-6 - alkyl group, and a halogen atom; and A means a group:

wherein R ^{3 represents} a C _1-6 alkyl group or a phenyl C _1-6 alkyl group. A triazolopurine derivative according to claim 1, wherein A is the following group:

A triazolopurine derivative according to claim 2, wherein R ^{2 is} a pyridyl group, a furyl group, a styryl group, a naphthyl group which optionally has a hydroxyl group as a substituent, a phenyl group which optionally has a group as a substituent selected from a C _1-6 alkyl group, NC _1-6 alkylamino group, N, N-di-C _1-6 alkylamino group, N-phenyl-C _1-6 alkylamino group, N, N-bisphenyl-C _1-6 alkylamino group, phenyl group , Phenoxy group, phenyl-C _1-6 alkoxy group, halogen-substituted C _1-6 alkyl group, halogen-substituted C _1-6 alkoxy group, di-C _1-6 alkylphosphorylmethyl group, C _1-6 - Is alkylthio group, hydroxy group and a halogen atom, a phenyl group substituted with a hydroxyl group and a halogen atom, or a phenyl group with 1 to 3 C _1-6 alkoxy groups as substituents. Triazolopurine derivative according to claim 3, which is selected from the group of the following compounds (a), (b) and (c): (a) a compound in which R ^{1 is} an alkyl group or a C _1-6 alkyl-substituted phenyl group and R ² is a phenyl group; (b) a compound in which R ^{1 is} an n-butyl group and R ² is a pyridyl group, a furyl group, a styryl group, a naphthyl group which optionally has a hydroxy group as a substituent, a phenyl group which optionally has a group as a substituent, selected from a C _1-6 alkyl group, NC _1-6 alkylamino group, N, N-di-C _1-6 alkylamino group, N-phenyl-C _1-6 alkylamino group, N, N-bisphenyl -C _1-6 alkylamino group, phenyl group, phenoxy group, phenyl-C _1-6 alkoxy group, halogen-substituted C1-6 alkyl group, halogen-substituted C _1-6 alkoxy group, di-C _1-6 alkylphosphorylmethyl group, C _1-6 alkylthio group, hydroxy group and a halogen atom, a phenyl group substituted with a hydroxy group and a halogen atom, or a phenyl group with 1 to 3 C _1-6 alkoxy groups as substituents, and (c) a compound wherein R ^{1 is} a phenyl group and R ² is a phenyl group having 3 C _1-6 alkoxy groups. Triazolopurine derivative according to claim 4, which is selected from the group of the following compounds (i) and (ii): (i) a compound in which R ^{1 is} a C _1-6 alkyl group and R ^{2 is} a phenyl group, and (ii) one A compound in which R ^{1 is} an n-butyl group and R ² is a naphthyl group optionally having a hydroxy group as a substituent, a phenyl group optionally having a group as a substituent selected from a C _1-6 alkyl group, N, N- Di-C _1-6 alkylamino group, N-phenyl-C _1-6 alkylamino group, phenyl group, phenoxy group, phenyl-C _1-6 alkoxy group, halogen-substituted C _1-6 alkyl group, halogen -substituted C _1-6 alkoxy group, di-C _1-6 alkylphosphorylmethyl group, C _1-6 alkylthio group and a halogen atom, a phenyl group substituted with a hydroxy group and a halogen atom, or a phenyl group with 1 to 3 C _{1 -6} alkoxy groups as substituents. Triazolopurine derivative according to claim 5, which is selected from 5-n-butyl-8- (3,4,5-trimethoxyphenyl) -1H-1,2,4-triazolo [5,1-i] purine, 5-n-butyl-8- (4-chlorophenyl) -1H-1,2,4-triazolo [5,1-i] purine, 5-n-butyl-8- (4-methoxyphenyl) -1H-1,2,4-triazolo [5,1-i] purine, 5-n-butyl-8- [4- (N, N-dimethylamino) phenyl] -1H-1,2,4-triazolo [5,1-i] purine, 5-n-butyl-8- (4-propoxyphenyl) -1H-1,2,4-triazolo [5,1-i] purine, 5-n-butyl-8- (4-ethoxyphenyl) -1H-1,2,4-triazolo [5,1-i] purine, 8- (4-biphenylyl) -5-n-butyl-1H-1,2,4-triazolo [5,1-i] purine, 5-n-butyl-8- (4-trifluoromethylphenyl) -1H-1,2,4-triazolo [5,1-i] purine and 5-n-pentyl-8-phenyl-1H-1,2,4- triazolo [5,1-i] purin. Triazolopurine derivative according to claim 6, which is selected from 5-n-butyl-8- (4-methoxyphenyl) -1H-1,2,4-triazolo [5,1-i] purine, 5-n-butyl-8- (3,4,5-trimethoxyphenyl) -1H-1,2,4-triazolo [5,1-i] purin and 8- (4-biphenylyl) -5-n-butyl-1H-1,2,4-triazolo [5,1-i] purine. A pharmaceutical composition comprising the triazolopurine derivative according to one of the claims 1 to 7 and a pharmaceutically acceptable carrier. A3 receptor ligand comprising the triazolopurine derivative according to one of the claims 1 to 7 as an active ingredient. Remedies for Asthma comprising the triazolopurine derivative according to any one of claims 1 to 7 as an active ingredient. Use of the triazolopurine derivative according to one of claims 1 to 7 for the production of a Medicament for blocking or stimulating an adenosine A3 receptor.